Journal
ATHEROSCLEROSIS
Volume 236, Issue 2, Pages 426-429Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2014.07.027
Keywords
Obesity; Endothelial insulin resistance; Oxidative stress; Inflammation; Cardiovascular disease
Funding
- Karolinska Institute
- Italian Ministry of Education, University and Research, PRIN
- University of Rome Sapienza
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Objective: Obesity-induced insulin resistance (IR) precipitates cardiovascular disease (CVD). Impairment of insulin signalling in the endothelium is emerging as a trigger of IR but the underlying mechanisms remain elusive. The mitochondrial adaptor p66(Shc) drives endothelial dysfunction via reactive oxygen species (ROS) generation. This study investigates p66(Shc) role in obesity-induced impairment of endothelial insulin signalling. Methods: All experiments were performed in leptin-deficient (Lep(Ob/Ob)) and wild-type (WT) mice. Results: Endothelium-dependent relaxations to insulin were blunted in Lep(Ob/Ob) as compared to WT. Interestingly, in vivo gene silencing of p66(Shc) restored insulin response via IRS-1/Akt/eNOS pathway. Furthermore, p66(Shc) knockdown in endothelial cells isolated from Lep(Ob/Ob) mice attenuated ROS production, free fatty acids (FFA) oxidation and prevented dysregulation of redox-sensitive pathways such as nuclear factor-kappa-B (NF-kB), AGE precursor methylglyoxal and PGI(2) synthase. Conclusions: Targeting endothelial p66(Shc) may represent a promising strategy to prevent IR and CVD in obese individuals. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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